Trials like the dostarlimab study in rectal cancer and NICHE in colon cancer show neoadjuvant immunotherapy can induce profound responses in MSI-high tumors. This is creating a new paradigm where major surgery might be avoided entirely for some patients, marking a significant shift in treatment strategy.

Unlike the 100% complete clinical response seen in some rectal cancer trials, studies like NICHE-2 for MSI-high colon cancer show a lower pathologic complete response rate (around 68%). This crucial difference suggests non-operative management is far riskier in colon cancer and requires a distinct clinical approach.

In a study of neoadjuvant Dostarlamab for MSI-high tumors, 100% of rectal cancer patients achieved a clinical complete response, compared to 82% of colon cancer patients. Experts find this high degree of discordance surprising and currently lack a clear biological explanation, as such differences are not typically observed in the metastatic setting.

The RUBY trial surprisingly revealed that patients with p53-mutated tumors, a subset of the generally less responsive pMMR group, derive significant benefit from adding immunotherapy to chemotherapy, challenging previous assumptions about this molecular subtype.

While both are used, some oncologists consider Next-Generation Sequencing (NGS) the gold standard over Immunohistochemistry (IHC) for MSI testing. NGS provides tumor mutation burden (TMB) data, which can identify rare, ultra-hypermutated but technically microsatellite-stable (MSS) tumors that are likely to respond to immunotherapy but would be missed by IHC alone.

Retrospective data suggests patients with MSI-high rectal cancer might not just respond poorly to standard neoadjuvant chemoradiation (TNT), but their disease could actually progress. This makes immunotherapy a potentially safer and more effective first-line neoadjuvant choice, not just an alternative.

For MSI-high patients responding to immunotherapy, a lingering mass on a CT scan may not be active cancer. A negative ctDNA test can help confirm that the visible lesion is likely just scar tissue, potentially averting unnecessary surgery.

Analysis across multiple studies suggests that longer treatment durations with neoadjuvant immunotherapy, up to six months, are associated with higher rates of complete pathologic response in localized MSI-high colorectal cancer. This indicates that treatment duration is a critical variable for optimizing patient outcomes and designing future trials.

Unlike other cancers, re-treating with immunotherapy after recurrence is considered a viable strategy for dMMR endometrial cancer. Experts theorize that these tumors are constantly evolving and may benefit from a "re-education" of the immune system, challenging the conventional wisdom that progression on a drug class means permanent resistance.